[go: up one dir, main page]

US20080050726A1 - Methods for diagnosing pancreatic cancer - Google Patents

Methods for diagnosing pancreatic cancer Download PDF

Info

Publication number
US20080050726A1
US20080050726A1 US11/523,496 US52349606A US2008050726A1 US 20080050726 A1 US20080050726 A1 US 20080050726A1 US 52349606 A US52349606 A US 52349606A US 2008050726 A1 US2008050726 A1 US 2008050726A1
Authority
US
United States
Prior art keywords
gene
tissue
expression
genes
lung
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/523,496
Other languages
English (en)
Inventor
Yixin Wang
Dmitri Talantov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Diagnostics LLC
Original Assignee
Janssen Diagnostics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Diagnostics LLC filed Critical Janssen Diagnostics LLC
Priority to US11/523,496 priority Critical patent/US20080050726A1/en
Assigned to VERIDEX LLC reassignment VERIDEX LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TALANTOV, DMITRI, WANG, YIXIN
Publication of US20080050726A1 publication Critical patent/US20080050726A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/40—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for data related to laboratory analysis, e.g. patient specimen analysis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • Pancreatic cancer is a deadly disease which has a mortality rate in the United States of more than 27,000 people a year.
  • Lillemoe et al (2000) About 85% of those diagnosed with the disease have metastasis or spread of the disease beyond the pancreas and are almost impossible to cure with surgical resection. If the growth is found sooner it may be resected with a much better hope of cure. Only 20% of the tumors are resectable and the survival benefit of approved chemotherapy regiments is rather poor and the chances of a cure are usually 25% or less.
  • pancreatic carcinoma is difficult because of the similarities in radiological and imaging features and the lack of specific clinical symptoms for pancreatic carcinoma.
  • Neoplasms of the exocrine pancreas may arise from ductal, acinar and stromal cells. Eighty percent of pancreatic carcinomas are derived from ductal epithelium. 60% of these tumors are located in the head of the pancreas, 10% in the tail and 30% are located in the body of the pancreas or are diffuse. Warshau et al. (1992). Histologically, these tumors are graded as well as differentiated, moderately differentiated and poorly differentiated. Some tumors are classified as adenosquamous, mucinous, undifferentiated or undifferentiated with osteoblast-like giant cells. Gibson et al. (1978).
  • FIG. 1 depicts microarray data showing intensities of two genes in a panel of tissues.
  • PSCA Prostate stem cell antigen
  • F5 Coagulation factor V
  • the bar graphs show the intensity on the y-axis and the tissue on the x-axis.
  • Panc Ca pancreatic cancer
  • Panc N normal pancreas.
  • FIG. 2 depicts electropherograms obtained from an Agilent Bioanalyzer.
  • RNA was isolated from FFPE tissue using a three hour (A) or sixteen hour (B) proteinase K digestion.
  • Sample C22 (red) was a one-year old block while sample C23 (blue) was a five-year old block.
  • a size ladder is shown in green.
  • FIG. 3 depicts a comparison of Ct values obtained from three different qRTPCR methods: random hexamer priming in the reverse transcription followed by qPCR with the resulting cDNA (RH 2 step), gene-specific (reverse primer) priming in the reverse transcription followed by qPCR with the resulting cDNA (GSP 2 step), or gene-specific priming and qRTPCR in a one-step reaction (GSP 1 step).
  • RNA from eleven samples was divided into the three methods and RNA levels for three genes were measured: ⁇ -actin (A), HUMSPB (B), and TTF (C). The median Ct value obtained with each method is indicated by the solid line.
  • FIG. 4 depicts assay optimization.
  • a and B Electropherograms obtained from an Agilent Bioanalyzer. RNA was isolated from FFPE tissue using a three hour (A) or sixteen hour (B) proteinase K digestion. Sample C22 (red) was a one-year old block while sample C23 (blue) was a five-year old block. A size ladder is shown in green.
  • C and D Comparison of Ct values obtained from three different qRTPCR methods: random hexamer priming in the reverse transcription followed by qPCR with the resulting cDNA (RH 2 step), gene-specific (reverse primer) priming in the reverse transcription followed by qPCR with the resulting cDNA (GSP 2 step), or gene-specific priming and qRTPCR in a one-step reaction (GSP 1 step).
  • RNA from eleven samples was divided into the three methods and RNA levels for two genes were measured: ⁇ -actin (C), HUMSPB (D). The median Ct value obtained with each method is indicated by the solid line.
  • FIG. 5 is a heatmap showing the relative expression levels of the 10 Marker panel across 239 samples. Red indicates higher expression.
  • a Biomarker is any indicia of the level of expression of an indicated Marker gene.
  • the indicia can be direct or indirect and measure over- or under-expression of the gene given the physiologic parameters and in comparison to an internal control, normal tissue or another carcinoma.
  • Biomarkers include, without limitation, nucleic acids (both over and under-expression and direct and indirect).
  • nucleic acids as Biomarkers can include any method known in the art including, without limitation, measuring DNA amplification, RNA, micro RNA, loss of heterozygosity (LOH), single nucleotide polymorphisms (SNPs, Brookes (1999)), microsatellite DNA, DNA hypo- or hyper-methylation.
  • Biomarkers can include any method known in the art including, without limitation, measuring amount, activity, modifications such as glycosylation, phosphorylation, ADP-ribosylation, ubiquitination, etc., imunohistochemistry (IHC).
  • Other Biomarkers include imaging, cell count and apoptosis Markers.
  • the indicated genes provided herein are those associated with a particular tumor or tissue type.
  • a Marker gene may be associated with numerous cancer types but provided that the expression of the gene is sufficiently associated with one tumor or tissue type to be identified using the algorithm described herein to be specific for a particular origin, the gene can be used in the claimed invention to determine tissue of origin for a carcinoma of unknown primary origin (CUP).
  • CUP carcinoma of unknown primary origin
  • Numerous genes associated with one or more cancers are known in the art.
  • the present invention provides preferred Marker genes and even more preferred Marker gene combinations. These are described herein in detail.
  • tissue of origin means either the tissue type (lung, colon, etc.) or the histological type (adenocarcinoma, squamous cell carcinoma, etc.) depending on the particular medical circumstances and will be understood by anyone of skill in the art.
  • a Marker gene corresponds to the sequence designated by a SEQ ID NO when it contains that sequence.
  • a gene segment or fragment corresponds to the sequence of such gene when it contains a portion of the referenced sequence or its complement sufficient to distinguish it as being the sequence of the gene.
  • a gene expression product corresponds to such sequence when its RNA, mRNA, or cDNA hybridizes to the composition having such sequence (e.g. a probe) or, in the case of a peptide or protein, it is encoded by such mRNA.
  • a segment or fragment of a gene expression product corresponds to the sequence of such gene or gene expression product when it contains a portion of the referenced gene expression product or its complement sufficient to distinguish it as being the sequence of the gene or gene expression product.
  • Marker genes include one or more Marker genes.
  • Marker or “Marker gene” is used throughout this specification to refer to genes and gene expression products that correspond with any gene the over- or under-expression of which is associated with a tumor or tissue type.
  • the preferred Marker genes are described in more detail in Tables 1 and 15.
  • the present invention provides a method of diagnosing pancreatic cancers.
  • the present invention thus provides methods for determining the direction of therapy by identifying pancreatic cancers potentially early enough to avoid resection thus allowing for chemotherapeutic regimens.
  • the present invention further provides composition containing at least one isolated sequence selected from SEQ ID NOs: 39-41 and 43-45.
  • the present invention further provides kits for conducting an assay according to the methods provided herein and further containing Biomarker detection reagents.
  • the present invention further provides methods for measuring gene expression by generating the amplicons of SEQ ID NOs: 42 and 46 to determine gene expression and comparing levels of at least one of these amplicons to normal tissue gene expression to diagnose pancreatic cancer.
  • the present invention further provides microarrays or gene chips for performing the methods described herein.
  • the present invention further provides diagnostic/prognostic portfolios containing isolated nucleic acid sequences, their complements, or portions thereof of a combination of genes as described herein where the combination is sufficient to measure or characterize gene expression in a biological sample having metastatic cells relative to cells from different carcinomas or normal tissue.
  • Any method described in the present invention can further include measuring expression of at least one gene constitutively expressed in the sample.
  • the Markers for pancreatic cancer are coagulation factor V (F5), prostate stem cell antigen (PSCA), integrin, ⁇ 6 (ITGB6), kallikrein 10 (KLK10), claudin 18 (CLDN18), trio isoform (TR10), and hypothetical protein FLJ22041 similar to FK506 binding proteins (FKBP10).
  • F5 and PSCA are measured together.
  • Biomarkers for ITGB6, KLK10, CLDN18, TR10, and FKBP10 can be measured in addition to or in place of F5 and/or PSCA.
  • F5 is described for instance by 20040076955; 20040005563; and WO2004031412.
  • PSCA is described for instance by WO1998040403; 20030232350; and WO2004063355.
  • ITGB6 is described for instance by WO2004018999; and 6339148.
  • KLK10 is described for instance by WO2004077060; and 20030235820.
  • CLDN18 is described for instance by WO2004063355; and WO2005005601.
  • TR10 is described for instance by 20020055627.
  • FKBP10 is described for instance by WO2000055320.
  • the invention further provides a method for providing a prognosis by determining the presence of pancreatic cancer according to the methods described herein and identifying the corresponding prognosis therefor.
  • the invention further provides a method for finding Biomarkers comprising determining the expression level of a Marker gene in a particular metastasis, measuring a Biomarker for the Marker gene to determine expression thereof, analyzing the expression of the Marker gene according to the methods described herein and determining if the Marker gene is effectively specific for pancreatic cancer.
  • compositions comprising at least one isolated sequence selected from SEQ ID Nos: 39-46.
  • the invention further provides kits, articles, microarrays or gene chip, diagnostic/prognostic portfolios for conducting the assays described herein and patient reports for reporting the results obtained by the present methods.
  • nucleic acid sequences having the potential to express proteins, peptides, or mRNA such sequences referred to as “genes”
  • genes such sequences referred to as “genes”
  • assaying gene expression can provide useful information about the occurrence of important events such as tumorogenesis, metastasis, apoptosis, and other clinically relevant phenomena. Relative indications of the degree to which genes are active or inactive can be found in gene expression profiles.
  • the gene expression profiles of this invention are used to provide a diagnosis and treat patients for CUP.
  • the sample can be prepared by any method known in the art including, but not limited to, bulk tissue preparation and laser capture microdissection.
  • the bulk tissue preparation can be obtained for instance from a biopsy or a surgical specimen.
  • the gene expression measuring can also include measuring the expression level of at least one gene constitutively expressed in the sample.
  • the specificity is preferably at least about 40% and the sensitivity at least at least about 80%.
  • the pre-determined cut-off levels are at least about 1.5-fold over- or under-expression in the sample relative to benign cells or normal tissue.
  • the pre-determined cut-off levels have at least a statistically significant p-value over-expression in the sample having metastatic cells relative to benign cells or normal tissue, preferably the p-value is less than 0.05.
  • gene expression can be measured by any method known in the art, including, without limitation on a microarray or gene chip, nucleic acid amplification conducted by polymerase chain reaction (PCR) such as reverse transcription polymerase chain reaction (RT-PCR), measuring or detecting a protein encoded by the gene such as by an antibody specific to the protein or by measuring a characteristic of the gene such as DNA amplification, methylation, mutation and allelic variation.
  • PCR polymerase chain reaction
  • RT-PCR reverse transcription polymerase chain reaction
  • the microarray can be for instance, a cDNA array or an oligonucleotide array. All these methods and can further contain one or more internal control reagents.
  • the present invention provides a method of generating a pancreatic cancer prognostic patient report by determining the results of any one of the methods described herein and preparing a report displaying the results and patient reports generated thereby.
  • the report can further contain an assessment of patient outcome and/or probability of risk relative to the patient population.
  • Sample preparation requires the collection of patient samples.
  • Patient samples used in the inventive method are those that are suspected of containing diseased cells such as cells taken from a nodule in a fine needle aspirate (FNA) of tissue.
  • Bulk tissue preparation obtained from a biopsy or a surgical specimen and laser capture microdissection are also suitable for use.
  • Laser Capture Microdissection (LCM) technology is one way to select the cells to be studied, minimizing variability caused by cell type heterogeneity. Consequently, moderate or small changes in Marker gene expression between normal or benign and cancerous cells can be readily detected.
  • Samples can also comprise circulating epithelial cells extracted from peripheral blood. These can be obtained according to a number of methods but the most preferred method is the magnetic separation technique described in U.S. Pat. No. 6,136,182.
  • Preferred methods for establishing gene expression profiles include determining the amount of RNA that is produced by a gene that can code for a protein or peptide. This is accomplished by reverse transcriptase PCR (RT-PCR), competitive RT-PCR, real time RT-PCR, differential display RT-PCR, Northern Blot analysis and other related tests. While it is possible to conduct these techniques using individual PCR reactions, it is best to amplify complementary DNA (cDNA) or complementary RNA (cRNA) produced from mRNA and analyze it via microarray. A number of different array configurations and methods for their production are known to those of skill in the art and are described in for instance, U.S. Pat. Nos.
  • Microarray technology allows for the measurement of the steady-state mRNA level of thousands of genes simultaneously thereby presenting a powerful tool for identifying effects such as the onset, arrest, or modulation of uncontrolled cell proliferation.
  • Two microarray technologies are currently in wide use. The first are cDNA arrays and the second are oligonucleotide arrays. Although differences exist in the construction of these chips, essentially all downstream data analysis and output are the same.
  • the product of these analyses are typically measurements of the intensity of the signal received from a labeled probe used to detect a cDNA sequence from the sample that hybridizes to a nucleic acid sequence at a known location on the microarray.
  • the intensity of the signal is proportional to the quantity of cDNA, and thus mRNA, expressed in the sample cells.
  • mRNA mRNA
  • Analysis of the expression levels is conducted by comparing such signal intensities. This is best done by generating a ratio matrix of the expression intensities of genes in a test sample versus those in a control sample. For instance, the gene expression intensities from a diseased tissue can be compared with the expression intensities generated from benign or normal tissue of the same type. A ratio of these expression intensities indicates the fold-change in gene expression between the test and control samples.
  • the selection can be based on statistical tests that produce ranked lists related to the evidence of significance for each gene's differential expression between factors related to the tumor's original site of origin. Examples of such tests include ANOVA and Kruskal-Wallis.
  • the rankings can be used as weightings in a model designed to interpret the summation of such weights, up to a cutoff, as the preponderance of evidence in favor of one class over another. Previous evidence as described in the literature may also be used to adjust the weightings.
  • a preferred embodiment is to normalize each measurement by identifying a stable control set and scaling this set to zero variance across all samples.
  • This control set is defined as any single endogenous transcript or set of endogenous transcripts affected by systematic error in the assay, and not known to change independently of this error. All Markers are adjusted by the sample specific factor that generates zero variance for any descriptive statistic of the control set, such as mean or median, or for a direct measurement. Alternatively, if the premise of variation of controls related only to systematic error is not true, yet the resulting classification error is less when normalization is performed, the control set will still be used as stated. Non-endogenous spike controls could also be helpful, but are not preferred.
  • Gene expression profiles can be displayed in a number of ways. The most common is to arrange raw fluorescence intensities or ratio matrix into a graphical dendogram where columns indicate test samples and rows indicate genes. The data are arranged so genes that have similar expression profiles are proximal to each other. The expression ratio for each gene is visualized as a color. For example, a ratio less than one (down-regulation) appears in the blue portion of the spectrum while a ratio greater than one (up-regulation) appears in the red portion of the spectrum.
  • Commercially available computer software programs are available to display such data including “Genespring” (Silicon Genetics, Inc.) and “Discovery” and “Infer” (Partek, Inc.)
  • protein levels can be measured by binding to an antibody or antibody fragment specific for the protein and measuring the amount of antibody-bound protein.
  • Antibodies can be labeled by radioactive, fluorescent or other detectable reagents to facilitate detection. Methods of detection include, without limitation, enzyme-linked immunosorbent assay (ELISA) and immunoblot techniques.
  • ELISA enzyme-linked immunosorbent assay
  • the genes that are differentially expressed are either up regulated or down regulated in patients with carcinoma of a particular origin relative to those with carcinomas from different origins. Up regulation and down regulation are relative terms meaning that a detectable difference (beyond the contribution of noise in the system used to measure it) is found in the amount of expression of the genes relative to some baseline. In this case, the baseline is determined based on the algorithm. The genes of interest in the diseased cells are then either up regulated or down regulated relative to the baseline level using the same measurement method.
  • Diseased in this context, refers to an alteration of the state of a body that interrupts or disturbs, or has the potential to disturb, proper performance of bodily functions as occurs with the uncontrolled proliferation of cells.
  • someone is diagnosed with a disease when some aspect of that person's genotype or phenotype is consistent with the presence of the disease.
  • the act of conducting a diagnosis or prognosis may include the determination of disease/status issues such as determining the likelihood of relapse, type of therapy and therapy monitoring.
  • therapy monitoring clinical judgments are made regarding the effect of a given course of therapy by comparing the expression of genes over time to determine whether the gene expression profiles have changed or are changing to patterns more consistent with normal tissue.
  • Genes can be grouped so that information obtained about the set of genes in the group provides a sound basis for making a clinically relevant judgment such as a diagnosis, prognosis, or treatment choice. These sets of genes make up the portfolios of the invention. As with most diagnostic Markers, it is often desirable to use the fewest number of Markers sufficient to make a correct medical judgment. This prevents a delay in treatment pending further analysis as well unproductive use of time and resources.
  • One method of establishing gene expression portfolios is through the use of optimization algorithms such as the mean variance algorithm widely used in establishing stock portfolios. This method is described in detail in 20030194734. Essentially, the method calls for the establishment of a set of inputs (stocks in financial applications, expression as measured by intensity here) that will optimize the return (e.g., signal that is generated) one receives for using it while minimizing the variability of the return. Many commercial software programs are available to conduct such operations. “Wagner Associates Mean-Variance Optimization Application,” referred to as “Wagner Software” throughout this specification, is preferred. This software uses functions from the “Wagner Associates Mean-Variance Optimization Library” to determine an efficient frontier and optimal portfolios in the Markowitz sense is preferred. Markowitz (1952). Use of this type of software requires that microarray data be transformed so that it can be treated as an input in the way stock return and risk measurements are used when the software is used for its intended financial analysis purposes.
  • the process of selecting a portfolio can also include the application of heuristic rules.
  • such rules are formulated based on biology and an understanding of the technology used to produce clinical results. More preferably, they are applied to output from the optimization method.
  • the mean variance method of portfolio selection can be applied to microarray data for a number of genes differentially expressed in subjects with cancer. Output from the method would be an optimized set of genes that could include some genes that are expressed in peripheral blood as well as in diseased tissue. If samples used in the testing method are obtained from peripheral blood and certain genes differentially expressed in instances of cancer could also be differentially expressed in peripheral blood, then a heuristic rule can be applied in which a portfolio is selected from the efficient frontier excluding those that are differentially expressed in peripheral blood.
  • the rule can be applied prior to the formation of the efficient frontier by, for example, applying the rule during data pre-selection.
  • heuristic rules can be applied that are not necessarily related to the biology in question. For example, one can apply a rule that only a prescribed percentage of the portfolio can be represented by a particular gene or group of genes.
  • Commercially available software such as the Wagner Software readily accommodates these types of heuristics. This can be useful, for example, when factors other than accuracy and precision (e.g., anticipated licensing fees) have an impact on the desirability of including one or more genes.
  • the gene expression profiles of this invention can also be used in conjunction with other non-genetic diagnostic methods useful in cancer diagnosis, prognosis, or treatment monitoring.
  • other non-genetic diagnostic methods useful in cancer diagnosis, prognosis, or treatment monitoring.
  • a range of such Markers exists including such analytes as CA 27.29.
  • blood is periodically taken from a treated patient and then subjected to an enzyme immunoassay for one of the serum Markers described above. When the concentration of the Marker suggests the return of tumors or failure of therapy, a sample source amenable to gene expression analysis is taken.
  • FNA fine needle aspirate
  • Kits made according to the invention include formatted assays for determining the gene expression profiles. These can include all or some of the materials needed to conduct the assays such as reagents and instructions and a medium through which Biomarkers are assayed.
  • Articles of this invention include representations of the gene expression profiles useful for treating, diagnosing, prognosticating, and otherwise assessing diseases. These profile representations are reduced to a medium that can be automatically read by a machine such as computer readable media (magnetic, optical, and the like).
  • the articles can also include instructions for assessing the gene expression profiles in such media.
  • the articles may comprise a CD ROM having computer instructions for comparing gene expression profiles of the portfolios of genes described above.
  • the articles may also have gene expression profiles digitally recorded therein so that they may be compared with gene expression data from patient samples. Alternatively, the profiles can be recorded in different representational format. A graphical recordation is one such format. Clustering algorithms such as those incorporated in “DISCOVERY” and “INFER” software from Partek, Inc. mentioned above can best assist in the visualization of such data.
  • articles of manufacture are media or formatted assays used to reveal gene expression profiles. These can comprise, for example, microarrays in which sequence complements or probes are affixed to a matrix to which the sequences indicative of the genes of interest combine creating a readable determinant of their presence.
  • articles according to the invention can be fashioned into reagent kits for conducting hybridization, amplification, and signal generation indicative of the level of expression of the genes of interest for detecting cancer.
  • this dataset was filtered to retain only those genes with at least two present calls across the entire dataset. This filtering left 14,547 genes. 2,736 genes were determined to be overexpressed in pancreatic cancer versus normal pancreas with a p value of less than 0.05. Forty five genes of the 2,736 were also overexpressed by at least two-fold compared to the maximum intensity found from lung and colon tissues. Finally, six probe sets were found which were overexpressed by at least two-fold compared to the maximum intensity found from lung, colon, breast, and ovarian tissues.
  • this dataset was filtered to retain only those genes with no more than two present calls in breast, colon, lung, and ovarian tissues. This filtering left 4,654 genes. 160 genes of the 4,654 genes were found to have at least two present calls in the pancreatic tissues (normal and cancer). Finally, eight probe sets were selected which showed the greatest differential expression between pancreatic cancer and normal tissues.
  • a total of 260 FFPE metastasis and primary tissues were acquired from a variety of commercial vendors.
  • the samples tested included: 30 breast metastasis, 30 colorectal metastasis, 56 lung metastasis, 49 ovarian metastasis 43 pancreas metastasis, 18 prostate primary and 2 prostate metastases and 32 other origins (6 stomach, 6 kidney, 3 larynx, 2 liver, 1 esophagus, 1 pharynx, 1 bile duct, 1 pleura, 3 bladder, 5 melanoma, 3 lymphoma).
  • RNA isolation from paraffin tissue sections was based on the methods and reagents described in the High Pure RNA Paraffin Kit manual (Roche) with the following modifications.
  • Sample was DNase treated with the addition of 10 ⁇ l DNase incubation buffer, 2 ⁇ l of DNase I and incubated for 30 minutes at 37° C. DNase was inactivated following the addition of 20 ⁇ l of tissue lysis buffer, 18 ⁇ l 10% SDS and 40 ⁇ l Proteinase K. Again, 325 ⁇ l binding buffer and 325 ⁇ l ethanol was added to each sample that was then mixed, centrifuged and supernatant was added onto the filter column. Sequential washes and elution of RNA proceeded as stated above with the exception of 50 ⁇ l of elution buffer being used to elute the RNA.
  • RNA was centrifuged for 2 minutes at full speed and supernatant was removed into a fresh 1.5 ml Eppendorf tube. Samples were quantified by OD 260/280 readings obtained by a spectrophotometer and samples were diluted to 50 ng/ ⁇ l. The isolated RNA was stored in Rnase-free water at ⁇ 80° C. until use.
  • mRNA reference sequence accession numbers in conjunction with Oligo 6.0 were used to develop TaqMan® CUP assays (lung Markers: human surfactant, pulmonary-associated protein B (HUMPSPBA), thyroid transcription factor 1 (TTF1), desmoglein 3 (DSG3), colorectal Marker: cadherin 17 (CDH17), breast Markers: mammaglobin (MG), prostate-derived ets transcription factor (PDEF), ovarian Marker: wilms tumor 1 (WT1), pancreas Markers: prostate stem cell antigen (PSCA), coagulation factor V (F5), prostate Marker kallikrein 3 (KLK3)) and housekeeping assays beta actin ( ⁇ -Actin), hydroxymethylbilane synthase (PBGD).
  • lung Markers human surfactant, pulmonary-associated protein B (HUMPSPBA), thyroid transcription factor 1 (TTF1), desmoglein 3 (DSG3), colorectal Marker: cadherin 17 (CDH17
  • RNA quantitation of gene-specific RNA was carried out in a 384 well plate on the ABI Prism 7900HT sequence detection system (Applied Biosystems). For each thermo-cycler run calibrators and standard curves were amplified. Calibrators for each Marker consisted of target gene in vitro transcripts that were diluted in carrier RNA from rat kidney at 1 ⁇ 10 5 copies. Standard curves for housekeeping Markers consisted of target gene in vitro transcripts that were serially diluted in carrier RNA from rat kidney at 1 ⁇ 10 7 , 1 ⁇ 10 5 and 1 ⁇ 10 3 copies. No target controls were also included in each assay run to ensure a lack of environmental contamination. All samples and controls were run in duplicate.
  • qRTPCR was performed with general laboratory use reagents in a 10 ⁇ l reaction containing: RT-PCR Buffer (50 nM Bicine/KOH pH 8.2, 115 nM KAc, 8% glycerol, 2.5 mM MgCl 2 , 3.5 mM MnSO 4 , 0.5 mM each of dCTP, dATP, dGTP and dTTP), Additives (2 mM Tris-Cl pH 8, 0.2 mM Albumin Bovine, 150 mM Trehalose, 0.002% Tween 20), Enzyme Mix (2U Tth (Roche), 0.4 mg/ ⁇ l Ab TP6-25), Primer and Probe Mix (0.2 ⁇ M Probe, 0.5 ⁇ M Primers).
  • RT-PCR Buffer 50 nM Bicine/KOH pH 8.2, 115 nM KAc, 8% glycerol, 2.5 mM MgCl 2 , 3.5 mM MnSO 4 , 0.5
  • First strand synthesis was carried out using either 100 ng of random hexamers or gene specific primers per reaction.
  • 11.5 ⁇ l of Mix-1 (primers and 1 ug of total RNA) was heated to 65° C. for 5 minutes and then chilled on ice.
  • 8.5 ⁇ l of Mix-2 (1 ⁇ Buffer, 0.01 mM DTT, 0.5 mM each dNTP's, 0.25 U/ ⁇ l RNasin®, 10U/ ⁇ l Superscript III) was added to Mix-1 and incubated at 50° C. for 60 minutes followed by 95° C. for 5 minutes.
  • the cDNA was stored at ⁇ 20° C. until ready for use.
  • qRTPCR for the second step of the two-step reaction was performed as stated above with the following cycling parameters: 1 cycle at 95° C. for 1 minute; 40 cycles of 95° C. for 15 seconds, 58° C. for 30 seconds.
  • qRTPCR for the one-step reaction was performed exactly as stated in the preceding paragraph. Both the one-step and two-step reactions were performed on 100 ng of template (RNA/cDNA). After the PCR reaction was completed, baseline and threshold values were set in the ABI 7900HT Prism software and calculated Ct values were exported to Microsoft Excel.
  • the minimal ⁇ Ct for each tissue of origin Marker set was determined for each sample.
  • the tissue of origin with the overall minimal ⁇ Ct was scored one and all other tissue of origins scored zero. Data were sorted according to pathological diagnosis. Partek Pro was populated with the modified feasibility data and an intensity plot was generated.
  • pancreas Marker candidates were analyzed: prostate stem cell antigen (PSCA), serine proteinase inhibitor, clade A member 1 (SERPINA1), cytokeratin 7 (KRT7), matrix metalloprotease 11 (MMP11), and mucin4 (MUC4) (Varadhachary et al (2004); Fukushima et al. (2004); Argani et al. (2001); Jones et al. (2004); Prasad et al. (2005); and Moniaux et al.
  • PSCA prostate stem cell antigen
  • SERPINA1 serine proteinase inhibitor
  • KRT7 cytokeratin 7
  • MMP11 matrix metalloprotease 11
  • MUC4 mucin4
  • microarray data on snap frozen, primary tissue serves as a good indicator of the ability of the Marker to identify a FFPE metastasis as being pancreatic in origin using qRTPCR but that additional Markers may be useful for optimal performance.
  • pancreatic ductal adenocarcinoma develops from ductal epithelial cells that comprise only a small percentage of all pancreatic cells (with acinar cells and islet cells comprising the majority) and because pancreatic adenocarcinoma tissues contain a significant amount of adjacent normal tissue (Prasad et al. (2005); and Ishikawa et al. (2005)), it has been difficult to identify pancreatic cancer Markers (i.e., upregulated in cancer) which would also differentiate this organ from the organs. For use in a CUP panel such differentiation is necessary.
  • the first query method returned six probe sets: coagulation factor V (F5), a hypothetical protein FLJ22041 similar to FK506 binding proteins (FKBP10), ⁇ 6 integrin (ITGB6), transglutaminase 2 (TGM2), heterogeneous nuclear ribonucleoprotein A0 (HNRP0), and BAX delta (BAX).
  • the second query method returns eight probe sets: F5, TGM2, paired-like homeodomain transcription factor 1 (PITX1), trio isoform mRNA (TRIO), mRNA for p73H (p73), an unknown protein for MGC:10264 (SCD), and two probe sets for claudin18.
  • F5 and TGM2 were present in both query results and, of the two, F5 looked the most promising ( FIG. 1B ).
  • RNA isolation and qRTPCR methods were optimized using fixed tissues before examining Marker panel performance.
  • optimization of the RTPCR reaction conditions can generate lower Ct values, which may help in analyzing older paraffin blocks (Cronin et al (2004)), and a one step RTPCR reaction with gene-specific primers can generate Ct values comparable to those generated in the corresponding two step reaction.
  • qRTPCR reactions (10 Markers and two housekeeping genes) were performed on 239 FFPE metastases.
  • the Markers used for the assay are shown in Table 2.
  • the lung Markers were human surfactant pulmonary-associated protein B (HUMPSPB), thyroid transcription factor 1 (TTF1), and desmoglein 3 (DSG3).
  • the colorectal Marker was cadherin 17 (CDH17).
  • the breast Markers were mammaglobin (MG) and prostate-derived Ets transcription factor (PDEF).
  • the ovarian Marker was Wilms tumor 1 (WT1).
  • the pancreas Markers were prostate stem cell antigen (PSCA) and coagulation factor V (F5), and the prostate Marker was kallikrein 3 (KLK3).
  • PSCA prostate stem cell antigen
  • F5 coagulation factor V
  • KLK3 kallikrein 3
  • microarray-based expression profiling was used on primary tumors to identify candidate Markers for use with metastases.
  • the fact that primary tumors can be used to discover tumor of origin Markers for metastases is consistent with several recent findings. For example, Weigelt and colleagues have shown that gene expression profiles of primary breast tumors are maintained in distant metastases. Weigelt et al. (2003). Italiano and coworkers found that EGFR status, as assessed by IHC, was similar in 80 primary colorectal tumors and the 80 related metastases. Italiano et al. (2005). Only five of the 80 showed discordance in EGFR status. Italiano et al. (2005).
  • PSCA could be used as a tumor of origin Marker for pancreas and prostate.
  • strong expression of PSCA is found in some prostate tissues at the RNA level but, because by including PSA in the assay, one can now segregate prostate and pancreatic cancers.
  • F5 was used as a complementary (to PSCA) Marker for pancreatic tissue of origin. In both the microarray data set with primary tissue and the qRTPCR data set with FFPE metastases, F5 was found to complement PSCA ( FIG. 4 and Table 3)
  • Pancreatic ductal adenocarcinoma develops from ductal epithelial cells that comprise only a small percentage of all pancreatic cells (with acinar and islet cells comprising the majority) in the normal pancreas. Furthermore, pancreatic adenocarcinoma tissues contain a significant amount of adjacent normal tissue. Prasad et al. (2005); and Ishikawa et al. (2005). Because of this the candidate pancreas Markers were enriched for genes elevated in pancreas adenocarcinoma relative to normal pancreas cells.
  • the first query method returned six probe sets: coagulation factor V (F5), a hypothetical protein FLJ22041 similar to FK506 binding proteins (FKBP10), beta 6 integrin (ITGB6), transglutaminase 2 (TGM2), heterogeneous nuclear ribonucleoprotein A0 (HNRP0), and BAX delta (BAX).
  • the second query method (see Materials and Methods section for details) returned eight probe sets: F5, TGM2, paired-like homeodomain transcription factor 1 (PITX1), trio isoform mRNA (TRIO), mRNA for p73H (p73), an unknown protein for MGC:10264 (SCD), and two probe sets for claudin18.
  • tissue specific Marker candidates were selected for further RT-PCR validation on metastatic carcinoma FFPE tissues by qRT-PCR. Marker candidates were tested on 205 FFPE metastatic carcinomas, from lung, pancreas, colon, breast, ovary, prostate and prostate primary carcinomas. Table 4 provides the gene symbols of the tissue specific Markers selected for RT-PCR validation and also summarizes the results of testing performed with these Markers.
  • the lung Markers were human surfactant pulmonary-associated protein B (HUMPSPB), thyroid transcription factor 1 (TTF1), and desmoglein 3 (DSG3).
  • the pancreas Markers were prostate stem cell antigen (PSCA) and coagulation factor V (F5), and the prostate Marker was kallikrein 3 (KLK3).
  • the colorectal Marker was cadherin 17 (CDH17).
  • Breast Markers were mammaglobin (MG) and prostate-derived Ets transcription factor (PDEF).
  • the ovarian Marker was Wilms tumor 1 (WT1).
  • RNA isolation and qRTPCR methods were optimized using fixed tissues before examining the performance of the Marker panel.
  • RNA was isolated from a five-year-old block (C23), a larger fraction of higher molecular weight RNAs were observed, as assessed by the hump in the shoulder, when the shorter proteinase K digest was used. This trend generally held when other samples were processed, regardless of the organ of origin for the FFPE metastasis. In conclusion, shortening the proteinase K digestion time does not sacrifice RNA yields and may aid in isolating longer, less degraded RNA.
  • tissue of origin was predicted correctly for 204 out of 260 tested samples with an overall accuracy of 78%.
  • a significant proportion of the false positive calls were due to the Markers' cross-reactivity in histologically similar tissues.
  • three squamous cell metastatic carcinomas originated from pharynx, larynx and esophagus were wrongly predicted as lung due to DSG3 expression in these tissues.
  • tissue of origin prediction was, with only a few exceptions, consistent with the known primary or tissue of origin diagnosis assessed by clinical/pathological evaluation including IHC. Similar to the training set, the assay was not able to differentiate squamous cell carcinomas originating from different sources and falsely predicted them as lung.
  • the assay also made putative tissue of origin diagnoses for eight out of eleven samples which remained CUP after standard diagnostic tests.
  • One of the CUP cases was especially interesting.
  • a male patient with a history of prostate cancer was diagnosed with metastatic carcinoma in lung and pleura.
  • Serum PSA tests and IHC with PSA antibodies on metastatic tissue were negative, so the pathologist's diagnosis was CUP with an inclination toward gastrointestinal tumors.
  • the assay strongly (posterior probability 0.99) predicted the tissue of origin as colon.
  • microarray-based expression profiling on primary tumors was used to identify candidate Markers for use with metastases.
  • the fact that primary tumors can be used to discover tumor of origin Markers for metastases is consistent with several recent findings.
  • Weigelt and colleagues have shown that gene expression profiles of primary breast tumors are maintained in distant metastases.
  • Backus and colleagues identified putative Markers for detecting breast cancer metastasis using a genome-wide gene expression analysis of breast and other tissues and demonstrated that mammaglobin and CK19 detected clinically actionable metastasis in breast sentinel lymph nodes with 90% sensitivity and 94% specificity.
  • Backus et al. (2005) The fact that primary tumors can be used to discover tumor of origin Markers for metastases.
  • Weigelt and colleagues have shown that gene expression profiles of primary breast tumors are maintained in distant metastases.
  • Backus and colleagues identified putative Markers for detecting
  • the qRTPCR protocol has been improved through the use of gene-specific primers in a one-step reaction.
  • This is the first demonstration of the use of gene-specific primers in a one-step qRTPCR reaction with FFPE tissue.
  • Other investigators have either done a two-step qRTPCR (cDNA synthesis in one reaction followed by qPCR) or have used random hexamers or truncated gene-specific primers.
  • Table 7 shows the Markers identified for the tissue origins indicated. For gene descriptions see Table 15.
  • the sample set included a total of 299 metastatic colon, breast, pancreas, ovary, prostate, lung and other carcinomas and primary prostate cancer samples. QC based on histological evaluation, RNA yield and expression of control gene beta-actin was implemented. Other samples category included metastasis originated from stomach (5), kidney (6), cholangio/gallbladder (4), liver (2), head and neck (4), ileum (1) carcinomas and one mesothelioma. Table 8 summarizes the results.
  • the male set included: SP_B, TTF1, DSG3, PSCA, F5, PSA, HPT1; the female set included: SP_B, TTF1, DSG3, PSCA, F5, HPT1, MGB, PDEF, WT1. Background expression was excluded from the assay results: Lung: SP_B, TTF1, DSG3; Ovary: WT1; and Colon: HPT1.
  • the CUP model was adjusted to the CUP prevalence (%): lung 23, pancreas 16, colorectal 9, breast 3, ovarian 4, prostate 2, other 43.
  • the prevalence for breast and ovarian adjusted to 0% for male patients, and prostate adjusted to 0% for female patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Pathology (AREA)
  • Biomedical Technology (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Oncology (AREA)
  • General Physics & Mathematics (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Hospice & Palliative Care (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
US11/523,496 2005-09-19 2006-09-19 Methods for diagnosing pancreatic cancer Abandoned US20080050726A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/523,496 US20080050726A1 (en) 2005-09-19 2006-09-19 Methods for diagnosing pancreatic cancer

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US71850105P 2005-09-19 2005-09-19
US72568005P 2005-10-12 2005-10-12
US11/523,496 US20080050726A1 (en) 2005-09-19 2006-09-19 Methods for diagnosing pancreatic cancer

Publications (1)

Publication Number Publication Date
US20080050726A1 true US20080050726A1 (en) 2008-02-28

Family

ID=37889439

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/523,496 Abandoned US20080050726A1 (en) 2005-09-19 2006-09-19 Methods for diagnosing pancreatic cancer
US11/523,495 Abandoned US20070065859A1 (en) 2005-09-19 2006-09-19 Methods and materials for identifying the origin of a carcinoma of unknown primary origin

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/523,495 Abandoned US20070065859A1 (en) 2005-09-19 2006-09-19 Methods and materials for identifying the origin of a carcinoma of unknown primary origin

Country Status (9)

Country Link
US (2) US20080050726A1 (es)
EP (3) EP2402758B1 (es)
JP (2) JP2009508493A (es)
BR (2) BRPI0616211A2 (es)
CA (2) CA2623775A1 (es)
DK (2) DK2402758T3 (es)
ES (2) ES2494843T3 (es)
HK (1) HK1128524A1 (es)
WO (2) WO2007035676A2 (es)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9212228B2 (en) 2005-11-24 2015-12-15 Ganymed Pharmaceuticals Ag Monoclonal antibodies against claudin-18 for treatment of cancer
US9512232B2 (en) 2012-05-09 2016-12-06 Ganymed Pharmaceuticals Ag Antibodies against Claudin 18.2 useful in cancer diagnosis
US9775785B2 (en) 2004-05-18 2017-10-03 Ganymed Pharmaceuticals Ag Antibody to genetic products differentially expressed in tumors and the use thereof
US10414824B2 (en) 2002-11-22 2019-09-17 Ganymed Pharmaceuticals Ag Genetic products differentially expressed in tumors and the use thereof
WO2020205993A1 (en) * 2019-04-01 2020-10-08 The University Of North Carolina At Chapel Hill Purity independent subtyping of tumors (purist), a platform and sample type independent single sample classifier for treatment decision making in pancreatic cancer

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8535677B2 (en) 2006-06-06 2013-09-17 Oxford Biotherapeutics, Ltd. Antibody drug conjugate treatment of colorectal cancer
BRPI0807227A2 (pt) * 2007-02-01 2019-01-22 Veridex Llc métodos e materiais para identificação da origem de um carcinoma de origem primária desconhecida
WO2008147205A1 (en) * 2007-06-01 2008-12-04 Agendia B.V. Prognostic gene expression signature for non small cell lung cancer patients
WO2009021019A1 (en) * 2007-08-06 2009-02-12 Health Research Inc. Methods for analysis of pdef and survivin as interconnected cancer biomarkers and targets for personalized medicine
WO2009046739A1 (en) 2007-10-09 2009-04-16 Curevac Gmbh Composition for treating prostate cancer (pca)
EP3222290A1 (en) * 2007-10-09 2017-09-27 CureVac AG Composition for treating prostate cancer (pca)
KR20100105770A (ko) * 2008-01-22 2010-09-29 베리덱스, 엘엘씨 전립선암에서 ｇｓｔｐ１ 과메틸화의 검출
WO2010037408A1 (en) 2008-09-30 2010-04-08 Curevac Gmbh Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof
US9207242B2 (en) * 2008-10-09 2015-12-08 The University Of Hong Kong Cadherin-17 as diagnostic marker and therapeutic target for liver cancer
KR100996143B1 (ko) 2008-10-31 2010-11-24 한국전기연구원 자계 고노출 직업군의 개인노출자계 추정방법
EP2667194A3 (en) 2009-01-14 2014-06-04 The United States of America, as represented by The Secretary, Department of Health and Human Services Ratio based biomarkers and methods of use thereof
MA33276B1 (fr) 2009-04-20 2012-05-02 Oxford Biotherapeutics Ltd Anticorps spécifiques à la cadhérine-17
US11348662B2 (en) 2009-05-20 2022-05-31 Koninklijke Philips N.V. Biomarkers based on sets of molecular signatures
US9151762B2 (en) 2009-06-12 2015-10-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Identification of DSG-3 as a biomarker for the detection of metastasis in lymph nodes
US20130078642A1 (en) * 2010-06-03 2013-03-28 Porto Conte Richerche S.R.L. Biomarkers for lung neuroendocrine tumors
US20140141996A1 (en) * 2011-06-22 2014-05-22 Oncocyte Corporation Methods and Compositions for the Treatment and Diagnosis of Cancer
WO2013174404A1 (en) 2012-05-23 2013-11-28 Ganymed Pharmaceuticals Ag Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
MX2014014356A (es) 2012-05-24 2015-07-06 Fundació Inst D Investigació Biomédica De Bellvitge Idibell Metodo para la identificacion del origen de un cancer de origen primario desconocido.
US20140072971A1 (en) * 2012-08-30 2014-03-13 Abbott Laboratories Prame detection assays
KR102643443B1 (ko) 2012-11-13 2024-03-06 비온테크 에스이 클라우딘 발현 암 질환의 치료제
KR20180043401A (ko) * 2013-01-22 2018-04-27 오츠카 세이야쿠 가부시키가이샤 WT1 mRNA의 발현량 정량 방법
WO2014127785A1 (en) 2013-02-20 2014-08-28 Ganymed Pharmaceuticals Ag Combination therapy involving antibodies against claudin 18.2 for treatment of cancer
CN114592060A (zh) * 2013-03-15 2022-06-07 詹森药业有限公司 预测性生物标记的测定法
WO2014146672A1 (en) 2013-03-18 2014-09-25 Ganymed Pharmaceuticals Ag Therapy involving antibodies against claudin 18.2 for treatment of cancer
EP3159695A3 (en) * 2013-06-20 2017-07-05 The Trustees of The University of Pennsylvania Methods for diagnosing pancreatic cancer
JP6443937B2 (ja) 2013-10-28 2018-12-26 株式会社サリバテック 膵癌用唾液バイオマーカー、及び、これを用いた膵癌患者を健常者から識別する方法
JP2016535989A (ja) 2013-11-01 2016-11-24 ファイザー・インク 前立腺関連抗原を発現させるためのベクター
JP6410343B2 (ja) * 2014-07-01 2018-10-24 学校法人順天堂 脂肪組織由来幹細胞から表皮角化細胞への誘導
CN116798520B (zh) * 2023-06-28 2024-08-23 复旦大学附属肿瘤医院 鳞状细胞癌组织起源位点蛋白标志物预测模型的构建方法

Citations (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5242974A (en) * 1991-11-22 1993-09-07 Affymax Technologies N.V. Polymer reversal on solid surfaces
US5384261A (en) * 1991-11-22 1995-01-24 Affymax Technologies N.V. Very large scale immobilized polymer synthesis using mechanically directed flow paths
US5405783A (en) * 1989-06-07 1995-04-11 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of an array of polymers
US5412087A (en) * 1992-04-24 1995-05-02 Affymax Technologies N.V. Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces
US5424186A (en) * 1989-06-07 1995-06-13 Affymax Technologies N.V. Very large scale immobilized polymer synthesis
US5429807A (en) * 1993-10-28 1995-07-04 Beckman Instruments, Inc. Method and apparatus for creating biopolymer arrays on a solid support surface
US5436327A (en) * 1988-09-21 1995-07-25 Isis Innovation Limited Support-bound oligonucleotides
US5472672A (en) * 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5527681A (en) * 1989-06-07 1996-06-18 Affymax Technologies N.V. Immobilized molecular synthesis of systematically substituted compounds
US5532128A (en) * 1991-11-19 1996-07-02 Houston Advanced Research Center Multi-site detection apparatus
US5545531A (en) * 1995-06-07 1996-08-13 Affymax Technologies N.V. Methods for making a device for concurrently processing multiple biological chip assays
US5554501A (en) * 1992-10-29 1996-09-10 Beckman Instruments, Inc. Biopolymer synthesis using surface activated biaxially oriented polypropylene
US5556752A (en) * 1994-10-24 1996-09-17 Affymetrix, Inc. Surface-bound, unimolecular, double-stranded DNA
US5561071A (en) * 1989-07-24 1996-10-01 Hollenberg; Cornelis P. DNA and DNA technology for the construction of networks to be used in chip construction and chip production (DNA-chips)
US5571639A (en) * 1994-05-24 1996-11-05 Affymax Technologies N.V. Computer-aided engineering system for design of sequence arrays and lithographic masks
US5599695A (en) * 1995-02-27 1997-02-04 Affymetrix, Inc. Printing molecular library arrays using deprotection agents solely in the vapor phase
US5642711A (en) * 1996-02-15 1997-07-01 Automated Waste Equipment Co., Inc. Apparatus for automatically controlling operation of the throttle assembly of a motor vehicle engine system during operation of power take-off equipment
US5658734A (en) * 1995-10-17 1997-08-19 International Business Machines Corporation Process for synthesizing chemical compounds
US5700637A (en) * 1988-05-03 1997-12-23 Isis Innovation Limited Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays
US5804604A (en) * 1989-12-21 1998-09-08 Biogen, Inc. Tat-derived transport polypeptides and fusion proteins
US5837507A (en) * 1995-11-13 1998-11-17 The Regents Of The University Of California Hox-induced enhancement of in vivo and in vitro proliferative capacity and gene therapeutic methods
US6004755A (en) * 1998-04-07 1999-12-21 Incyte Pharmaceuticals, Inc. Quantitative microarray hybridizaton assays
US6218122B1 (en) * 1998-06-19 2001-04-17 Rosetta Inpharmatics, Inc. Methods of monitoring disease states and therapies using gene expression profiles
US6218114B1 (en) * 1998-03-27 2001-04-17 Academia Sinica Methods for detecting differentially expressed genes
US6339148B1 (en) * 1991-07-11 2002-01-15 The Regents Of The University Of California Isolated nucleic acid encoding an integrin β-subunit
US20020055627A1 (en) * 1999-03-12 2002-05-09 Rosen Craig A. Nucleic acids, proteins and antibodies
US20030194733A1 (en) * 2002-03-29 2003-10-16 Yixin Wang Cancer diagnostic panel
US20030212264A1 (en) * 1998-06-23 2003-11-13 Chiron Corporation Pancreatic cancer genes
US20030232350A1 (en) * 2001-11-13 2003-12-18 Eos Biotechnology, Inc. Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer
US20030235820A1 (en) * 2001-02-27 2003-12-25 Eos Biotechnology, Inc. Novel methods of diagnosis of metastatic colorectal cancer, compositions and methods of screening for modulators of metastatic colorectal cancer
US20040005563A1 (en) * 2001-06-18 2004-01-08 Eos Biotechnology, Inc. Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer
US20040021572A1 (en) * 2002-08-05 2004-02-05 Schoen Marc L. Electronic baggage tracking and identification
US20040076955A1 (en) * 2001-07-03 2004-04-22 Eos Biotechnology, Inc. Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer
US20040219572A1 (en) * 2002-12-17 2004-11-04 Jie Chen Specific markers for pancreatic cancer
US20050009067A1 (en) * 2003-05-19 2005-01-13 Craig Logsdon Expression profile of pancreatic cancer
US20050260639A1 (en) * 2002-09-30 2005-11-24 Oncotherapy Science, Inc. Method for diagnosing pancreatic cancer
US20060029987A1 (en) * 2004-08-06 2006-02-09 Applera Corporation Diagnosis of pancreatic cancer by using pancreatic targets
US20060269921A1 (en) * 2003-02-18 2006-11-30 Davendra Segara Methods of diagnosis and prognosis of pancreatic cancer
US7427603B2 (en) * 2002-09-26 2008-09-23 The Children's Medical Center Corporation Method of enhancing proliferation and/or hematopoietic differentiation of stem cells

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0453560B1 (en) 1989-11-13 1999-05-26 Massachusetts Institute Of Technology Localization and characterization of the wilms' tumor gene
US5786148A (en) 1996-11-05 1998-07-28 Incyte Pharmaceuticals, Inc. Polynucleotides encoding a novel prostate-specific kallikrein
US5624711A (en) 1995-04-27 1997-04-29 Affymax Technologies, N.V. Derivatization of solid supports and methods for oligomer synthesis
US5668267A (en) 1995-05-31 1997-09-16 Washington University Polynucleotides encoding mammaglobin, a mammary-specific breast cancer protein
ES2242221T3 (es) 1996-04-16 2005-11-01 Kishimoto, Tadamitsu Procedimiento para la deteccion de celulas de cancer solido y de heterotipia histologica y procedimiento para el examen de tejidos destinados a trasplantes de medula osea y al trasplante de celulas madre sanguineas perifericas.
EP1514876B1 (en) 1997-03-10 2013-05-08 The Regents of The University of California Antibody against prostate stem cell antigen (PSCA)
AU7830598A (en) 1997-06-10 1998-12-30 Michael A. Levine Methods for thyroid cell detection
US20010010934A1 (en) 1998-07-31 2001-08-02 Towia Aron Libermann Prostate derived ets factor
US6232073B1 (en) 1999-02-05 2001-05-15 Virginia Commonwealth University Nucleic acid marker for cancer
AU3395900A (en) 1999-03-12 2000-10-04 Human Genome Sciences, Inc. Human lung cancer associated gene sequences and polypeptides
US6271002B1 (en) 1999-10-04 2001-08-07 Rosetta Inpharmatics, Inc. RNA amplification method
US20040146862A1 (en) 2000-03-15 2004-07-29 Eos Biotechnology, Inc. Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer
EP1311673A2 (en) 2000-03-27 2003-05-21 Corixa Corporation Compositions and methods for the therapy and diagnosis of prostate cancer
JP2004526154A (ja) 2001-03-12 2004-08-26 モノジェン インコーポレイテッド 細胞ベースの検出および病態の判別
US20030138793A1 (en) * 2001-06-10 2003-07-24 Irm Llc, A Delaware Limited Liability Company Molecular signatures of commonly fatal carcinomas
FR2826168B1 (fr) 2001-06-19 2003-12-05 Eads Airbus Sa Procede de realisation d'une couche acoustiquement resistive renforcee, couche resistive ainsi obtenue et panneau utilisant une telle couche
US7705120B2 (en) 2001-06-21 2010-04-27 Millennium Pharmaceuticals, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer
AU2002343443A1 (en) * 2001-09-28 2003-04-14 Whitehead Institute For Biomedical Research Classification of lung carcinomas using gene expression analysis
US20030215835A1 (en) 2002-01-15 2003-11-20 Zairen Sun Differentially-regulated prostate cancer genes
DE10230276B4 (de) 2002-07-05 2005-05-19 Daimlerchrysler Ag AS-Druckgusslegierung und Verfahren zum Herstellen eines Aggregatteils aus einer derartigen AS-Druckgusslegierung
EP1565581B1 (en) 2002-08-20 2011-08-10 Millennium Pharmaceuticals, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of cervical cancer
CA2500472A1 (en) 2002-09-30 2004-04-15 Oncotherapy Science, Inc. Genes and polypeptides relating to human pancreatic cancers
US20070224201A1 (en) 2002-10-02 2007-09-27 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
WO2004060302A2 (en) 2002-12-26 2004-07-22 Cemines, Llc. Methods and compositions for the diagnosis, prognosis, and treatment of cancer
US20050181375A1 (en) 2003-01-10 2005-08-18 Natasha Aziz Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of metastatic cancer
EP1601922B1 (en) 2003-02-26 2007-05-09 Delta Process Engineering APS Dual scraped, thin film, heat exchanger for viscous fluid
WO2004077060A2 (en) 2003-02-27 2004-09-10 Mount Sinai Hospital Assay for detection of renal cell carcinoma
US20060265138A1 (en) * 2003-03-14 2006-11-23 David Bowtell Expression profiling of tumours
US20060019256A1 (en) 2003-06-09 2006-01-26 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
US20050081341A1 (en) 2003-10-15 2005-04-21 Mcdougall William B.S. Woven touch fastener products
ES2323972T3 (es) * 2004-06-25 2009-07-28 Veridex, Llc Metodos y reactivos para la deteccion de melanoma.
US9667980B2 (en) 2005-03-01 2017-05-30 Qualcomm Incorporated Content-adaptive background skipping for region-of-interest video coding
BRPI0807227A2 (pt) * 2007-02-01 2019-01-22 Veridex Llc métodos e materiais para identificação da origem de um carcinoma de origem primária desconhecida

Patent Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5700637A (en) * 1988-05-03 1997-12-23 Isis Innovation Limited Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays
US5436327A (en) * 1988-09-21 1995-07-25 Isis Innovation Limited Support-bound oligonucleotides
US5527681A (en) * 1989-06-07 1996-06-18 Affymax Technologies N.V. Immobilized molecular synthesis of systematically substituted compounds
US5424186A (en) * 1989-06-07 1995-06-13 Affymax Technologies N.V. Very large scale immobilized polymer synthesis
US5405783A (en) * 1989-06-07 1995-04-11 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of an array of polymers
US5445934A (en) * 1989-06-07 1995-08-29 Affymax Technologies N.V. Array of oligonucleotides on a solid substrate
US5561071A (en) * 1989-07-24 1996-10-01 Hollenberg; Cornelis P. DNA and DNA technology for the construction of networks to be used in chip construction and chip production (DNA-chips)
US5804604A (en) * 1989-12-21 1998-09-08 Biogen, Inc. Tat-derived transport polypeptides and fusion proteins
US6339148B1 (en) * 1991-07-11 2002-01-15 The Regents Of The University Of California Isolated nucleic acid encoding an integrin β-subunit
US5532128A (en) * 1991-11-19 1996-07-02 Houston Advanced Research Center Multi-site detection apparatus
US5384261A (en) * 1991-11-22 1995-01-24 Affymax Technologies N.V. Very large scale immobilized polymer synthesis using mechanically directed flow paths
US5242974A (en) * 1991-11-22 1993-09-07 Affymax Technologies N.V. Polymer reversal on solid surfaces
US5412087A (en) * 1992-04-24 1995-05-02 Affymax Technologies N.V. Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces
US5554501A (en) * 1992-10-29 1996-09-10 Beckman Instruments, Inc. Biopolymer synthesis using surface activated biaxially oriented polypropylene
US5529756A (en) * 1993-10-22 1996-06-25 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5472672A (en) * 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5429807A (en) * 1993-10-28 1995-07-04 Beckman Instruments, Inc. Method and apparatus for creating biopolymer arrays on a solid support surface
US5571639A (en) * 1994-05-24 1996-11-05 Affymax Technologies N.V. Computer-aided engineering system for design of sequence arrays and lithographic masks
US5593839A (en) * 1994-05-24 1997-01-14 Affymetrix, Inc. Computer-aided engineering system for design of sequence arrays and lithographic masks
US5556752A (en) * 1994-10-24 1996-09-17 Affymetrix, Inc. Surface-bound, unimolecular, double-stranded DNA
US5599695A (en) * 1995-02-27 1997-02-04 Affymetrix, Inc. Printing molecular library arrays using deprotection agents solely in the vapor phase
US5545531A (en) * 1995-06-07 1996-08-13 Affymax Technologies N.V. Methods for making a device for concurrently processing multiple biological chip assays
US5658734A (en) * 1995-10-17 1997-08-19 International Business Machines Corporation Process for synthesizing chemical compounds
US5837507A (en) * 1995-11-13 1998-11-17 The Regents Of The University Of California Hox-induced enhancement of in vivo and in vitro proliferative capacity and gene therapeutic methods
US5642711A (en) * 1996-02-15 1997-07-01 Automated Waste Equipment Co., Inc. Apparatus for automatically controlling operation of the throttle assembly of a motor vehicle engine system during operation of power take-off equipment
US6218114B1 (en) * 1998-03-27 2001-04-17 Academia Sinica Methods for detecting differentially expressed genes
US6004755A (en) * 1998-04-07 1999-12-21 Incyte Pharmaceuticals, Inc. Quantitative microarray hybridizaton assays
US6218122B1 (en) * 1998-06-19 2001-04-17 Rosetta Inpharmatics, Inc. Methods of monitoring disease states and therapies using gene expression profiles
US20030212264A1 (en) * 1998-06-23 2003-11-13 Chiron Corporation Pancreatic cancer genes
US20020055627A1 (en) * 1999-03-12 2002-05-09 Rosen Craig A. Nucleic acids, proteins and antibodies
US20030235820A1 (en) * 2001-02-27 2003-12-25 Eos Biotechnology, Inc. Novel methods of diagnosis of metastatic colorectal cancer, compositions and methods of screening for modulators of metastatic colorectal cancer
US20040005563A1 (en) * 2001-06-18 2004-01-08 Eos Biotechnology, Inc. Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer
US20040076955A1 (en) * 2001-07-03 2004-04-22 Eos Biotechnology, Inc. Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer
US20030232350A1 (en) * 2001-11-13 2003-12-18 Eos Biotechnology, Inc. Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer
US20030194733A1 (en) * 2002-03-29 2003-10-16 Yixin Wang Cancer diagnostic panel
US20040021572A1 (en) * 2002-08-05 2004-02-05 Schoen Marc L. Electronic baggage tracking and identification
US7427603B2 (en) * 2002-09-26 2008-09-23 The Children's Medical Center Corporation Method of enhancing proliferation and/or hematopoietic differentiation of stem cells
US20050260639A1 (en) * 2002-09-30 2005-11-24 Oncotherapy Science, Inc. Method for diagnosing pancreatic cancer
US20040219572A1 (en) * 2002-12-17 2004-11-04 Jie Chen Specific markers for pancreatic cancer
US20060269921A1 (en) * 2003-02-18 2006-11-30 Davendra Segara Methods of diagnosis and prognosis of pancreatic cancer
US20050009067A1 (en) * 2003-05-19 2005-01-13 Craig Logsdon Expression profile of pancreatic cancer
US20060029987A1 (en) * 2004-08-06 2006-02-09 Applera Corporation Diagnosis of pancreatic cancer by using pancreatic targets

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10414824B2 (en) 2002-11-22 2019-09-17 Ganymed Pharmaceuticals Ag Genetic products differentially expressed in tumors and the use thereof
US9775785B2 (en) 2004-05-18 2017-10-03 Ganymed Pharmaceuticals Ag Antibody to genetic products differentially expressed in tumors and the use thereof
US10738108B2 (en) 2005-11-24 2020-08-11 Astellas Pharma Inc. Monoclonal antibodies against claudin-18 for treatment of cancer
US9751934B2 (en) 2005-11-24 2017-09-05 Ganymed Pharmaceuticals Ag Monoclonal antibodies against claudin-18 for treatment of cancer
US10017564B2 (en) 2005-11-24 2018-07-10 Ganymed Pharmaceuticals Gmbh Monoclonal antibodies against claudin-18 for treatment of cancer
US10174104B2 (en) 2005-11-24 2019-01-08 Ganymed Pharmaceuticals Gmbh Monoclonal antibodies against claudin-18 for treatment of cancer
US9499609B2 (en) 2005-11-24 2016-11-22 Ganymed Pharmaceuticals Ag Monoclonal antibodies against claudin-18 for treatment of cancer
US9212228B2 (en) 2005-11-24 2015-12-15 Ganymed Pharmaceuticals Ag Monoclonal antibodies against claudin-18 for treatment of cancer
US11739139B2 (en) 2005-11-24 2023-08-29 Astellas Pharma Inc. Monoclonal antibodies against Claudin-18 for treatment of cancer
US9512232B2 (en) 2012-05-09 2016-12-06 Ganymed Pharmaceuticals Ag Antibodies against Claudin 18.2 useful in cancer diagnosis
US10053512B2 (en) 2012-05-09 2018-08-21 Ganymed Pharmaceuticals Ag Antibodies against claudin 18.2 useful in cancer diagnosis
US11976130B2 (en) 2012-05-09 2024-05-07 Astellas Pharma Inc. Antibodies against claudin 18.2 useful in cancer diagnosis
WO2020205993A1 (en) * 2019-04-01 2020-10-08 The University Of North Carolina At Chapel Hill Purity independent subtyping of tumors (purist), a platform and sample type independent single sample classifier for treatment decision making in pancreatic cancer
US12000003B2 (en) 2019-04-01 2024-06-04 The University Of North Carolina At Chapel Hill Platform and sample type independent single sample classifier for treatment decision making in pancreatic ductal adenocarcinoma cancer

Also Published As

Publication number Publication date
CA2623775A1 (en) 2007-03-29
WO2007035676A3 (en) 2007-12-27
BRPI0616090A2 (pt) 2011-06-07
CA2623425A1 (en) 2007-03-29
ES2525545T3 (es) 2014-12-26
DK1934615T3 (da) 2014-07-14
DK2402758T3 (da) 2014-11-03
EP1934378A2 (en) 2008-06-25
EP1934615A2 (en) 2008-06-25
EP1934615B1 (en) 2014-06-04
US20070065859A1 (en) 2007-03-22
WO2007035690A2 (en) 2007-03-29
JP2009509502A (ja) 2009-03-12
EP1934378A4 (en) 2008-10-29
WO2007035690A3 (en) 2007-06-14
BRPI0616211A2 (pt) 2011-06-14
EP2402758A3 (en) 2012-10-31
EP2402758B1 (en) 2014-09-10
ES2494843T3 (es) 2014-09-16
JP2009508493A (ja) 2009-03-05
EP1934615A4 (en) 2009-02-11
WO2007035676A2 (en) 2007-03-29
EP2402758A2 (en) 2012-01-04
HK1128524A1 (zh) 2009-10-30
JP5405110B2 (ja) 2014-02-05

Similar Documents

Publication Publication Date Title
US20080050726A1 (en) Methods for diagnosing pancreatic cancer
US20170073758A1 (en) Methods and materials for identifying the origin of a carcinoma of unknown primary origin
US11549148B2 (en) Neuroendocrine tumors
Vachani et al. A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma
JP2009528825A (ja) デュークスｂ大腸がんの再発を予測するための分子的解析
JP2008521412A (ja) 肺癌予後判定手段
AU2008203226B2 (en) Colorectal cancer prognostics
US20090286240A1 (en) Biomarkers overexpressed in prostate cancer
WO2009089548A2 (en) Malignancy-risk signature from histologically normal breast tissue
JP2021506308A (ja) 遺伝子発現プロファイルを使用して肺癌を診断するための組成物および方法
JP7463357B2 (ja) Ｐｄｅ４ｄ７及びｄｈｘ９発現に基づく術前のリスク層別化
CA2475769C (en) Colorectal cancer prognostics
US8008012B2 (en) Biomarkers downregulated in prostate cancer
US8293469B2 (en) Biomarkers downregulated in prostate cancer
MX2008003933A (es) Metodos para diagnosticar el cancer pancreatico
WO2020188564A1 (en) Prognostic and treatment methods for prostate cancer
MX2008003932A (es) Metodos y materiales para identificar el origen de un carcinoma de origen primario desconocido

Legal Events

Date Code Title Description
AS Assignment

Owner name: VERIDEX LLC, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WANG, YIXIN;TALANTOV, DMITRI;REEL/FRAME:018496/0110

Effective date: 20061102

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION